Polyaromatic propynyl compounds and pharmaceutical/cosmetic compositions comprised thereof

ABSTRACT

Novel pharmaceutically/cosmetically-active polyaromatic propynyl compounds have the structural formula (1): ##STR1## in which X is one of the radicals: ##STR2## and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

CROSS-REFERENCE TO COMPANION APPLICATIONS

Copending applications Ser. No. 08/356,913 Attorney Docket No.016800-006! and Ser. No. 08/356,680 Attorney Docket No. 016800-008!,both filed concurrently herewith and assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to novel polyaromatic propynyl compoundsand to pharmaceutical/cosmetic compositions comprised thereof; thesubject compounds are especially useful in human or veterinary medicine,or alternatively in cosmetic compositions.

SUMMARY OF THE INVENTION

The compounds according to the invention display marked activity in thefields of cell differentiation and proliferation, and are particularlyuseful in the topical and systemic treatment of dermatologicalconditions associated with a keratinization disorder, dermatologicalconditions (and the like) including an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. The subject compounds can, in addition, beused for the treatment of degeneration diseases of the connectivetissue, for combating skin aging, whether photoinduced or chronologic,and for treating cicatrization disorders. They are also useful forophthalmological applications, especially for the treatment ofcorneopathies.

The compounds according to this invention can also be formulated intocosmetic compositions for body and hair care.

Briefly, the polyaromatic propynyl compounds according to this inventionhave the following structural formula (I): ##STR3## in which X is one ofthe radicals: ##STR4## wherein R₁₀ and R₁₁ are as defined below; Ar is aradical selected from among those of the following formulae (a)-(e):##STR5## wherein R₅ and R₆ are as defined below; R₁ is (i) a hydrogenatom, (ii) a radical --CH₃, (iii) a radical --CH₂ --O--R₆, (iv) aradical --O--R₆, (v) a radical --CO--R₇, or (vi) a radical --S(O)_(t) R₉wherein R₆, R₇, R₉ and t are as defined below; R₂ and R₃, which may beidentical or different, are each a hydrogen atom, a linear or branchedalkyl radical having from 1 to 20 carbon atoms, a radical --OR₆ or aradical --SR₆, wherein R₆ is as defined below, with the proviso that R₂and R₃ may together form, with the carbon atoms from which they depend,a 5- or 6-membered ring optionally substituted by methyl groups and/oroptionally interrupted by an oxygen or sulfur atom; R₄ is a hydrogenatom, a halogen atom, a lower alkyl radical or a radical --OR₆ whereinR₆ is as defined below; R₅ has the definition of R₄, with the provisothat R₄ and R₅ may be identical or different; R₆ is a hydrogen atom, alower alkyl radical or a radical --CO--R₉ wherein R₉ is as defined belowand further wherein the radicals R₆ may be identical or different; R₇ is(a) a hydrogen atom, (b) a lower alkyl radical, (c) a radical of theformula: ##STR6## wherein R' and R" are as defined below, or (d) aradical --OR₈ wherein R₈ is a hydrogen atom, a linear or branched alkylradical having from 1 to 20 carbon atoms, an alkenyl radical, a mono- orpolyhydroxyalkyl radical, an optionally substituted aryl or aralkylradical, or a sugar residue, or an amino acid or peptide residue; R₉ isa lower alkyl radical; R₁₀ is a hydrogen atom, a lower alkyl radical, ora radical --OR₆ ; R₁₁ is a radical --OR₆ ; R' and R", which may beidentical or different, are each a hydrogen atom, a lower alkyl radical,a mono or polyhydroxyalkyl radical, an optionally substituted arylradical or an amino acid or peptide or sugar residue, with the provisothat R' and R" may together form, with the nitrogen atom from which theydepend, a heterocycle; t is an integer equal to 0, 1 or 2; and with thefurther proviso that the radicals R₁₀ and R₁₁ may together form a singleoxo group of the formula ═O.

This invention also features the salts of the compounds of formula (I)in the event that R₁ is a carboxylic acid functional group, as well asthe optical and geometric isomers thereof. When the compounds accordingto the invention are in the form of salts, they are preferably salts ofan alkali or alkaline earth metal, or, alternatively, of zinc or of anorganic amine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1, 2 and 3 are reaction schemes/mechanisms illustrating synthesesfor the preparation of the polyaromatic propynyl compounds according tothe present invention.

DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THEINVENTION

More particularly according to the present invention, by "lower alkylradical" is intended an alkyl radical having from 1 to 6 carbon atoms,preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexylradicals.

By "linear or branched alkyl radical having from 1 to 20 carbon atoms"is preferably intended methyl, ethyl, propyl, 2-ethylhexyl, octyl,dodecyl, hexadecyl and octadecyl radicals.

By "monohydroxyalkyl radical" is intended a radical preferably having 2or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropyl or3-hydroxypropyl radical.

By "polyhydroxyalkyl radical" is intended a radical preferably having 3to 6 carbon atoms and 2 to 5 hydroxyl groups, such as2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4 5-tetrahydroxypentylradicals, or a pentaerythritol residue.

By "aryl radical" is preferably intended a phenyl radical optionallysubstituted by at least one halogen atom, or a hydroxyl or nitrofunctional group.

By "aralkyl radical" is preferably intended a benzyl or phenethylradical optionally substituted by at least one halogen atom, or ahydroxyl or nitro functional group.

By "alkenyl radical" is intended a radical preferably having from 1 to 5carbon atoms and one or more sites of ethylenic unsaturation, such as,more particularly, the allyl radical.

By "sugar residue" is intended a residue derived especially fromglucose, galactose or mannose, or alternatively from glucuronic acid.

By "amino acid residue" is especially intended a residue derived fromlysine, glycine or aspartic acid, and by "peptide residue" is moreparticularly intended a dipeptide or tripeptide residue prepared via thecombination of amino acids.

Lastly, by "heterocycle" is preferably intended a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted atthe 4-position by a C₁ -C₆ alkyl radical or a mono- or polyhydroxyalkylradical as defined above.

When R₄ and R₅ in formula (I) represent a halogen atom, it is preferablya fluorine, chlorine or bromine atom.

Among the compounds of formula (I) according to the present invention,particularly representative are the following:

Methyl 4-3-oxo-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

Methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

4-3-Oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

2-Hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

Methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

2-Hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

2-Hydroxy-4- 3-oxo-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoicacid;

4-1-Oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid;

4-1-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid;

Methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate;

2-Hydroxy-4-(3-oxo-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoicacid;

4- 3-Hydroxy-3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoic acid;

Methyl N-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate;

N-Methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)-1-propynyl!-2-pyrrolecarboxylicacid;

Methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate;

Methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate;

4- 1-Hydroxy-3-(4,4-dimethylthiochroman-6-yl)-2-propynyl!benzoic acid;

2-Hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid;

2-Hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoic acid;

(+)-Isomer of methyl4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

(-)-Isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

(+)-Isomer of methyl-2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

(-)-Isomer of 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

(-)-Isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

(-)-Isomer of methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

(+)-Isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

(+)-Isomer of2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

Methyl 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

2-Hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

2-Methoxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzaldehyde;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzylacetate;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzenemethanol;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!toluene;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!phenylacetate;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1propynyl!phenol;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfinylmethane;

4-3-Hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfonylmethane;

N-Ethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide;

N,N'-Diethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide;

Morpholide of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

Methyl 5-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-thiophenecarboxylate;

Methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoate;

2-Hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoicacid;

Methyl 2-hydroxy-4-3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;

2-Hydroxy-4-(3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

4- 3-Hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid;

4- 3-Hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoic acid;

Methyl 3-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-benzoate;

3-Methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

2-Chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

2-Acetoxy-4-3-acetoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid;

Methyl 4-3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl!benzoate;

Methyl 4-3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl!benzoate.

According to the present invention, the compounds of formula (I) whichare more particularly preferred are those in which R₅ represents --OH,R₇ represents a radical OR₈ and R₁₁ represents a radical

The present invention also features the processes for preparing thecompounds of formula (I) via the reaction schemes or mechanismsillustrated in FIGS. 1, 2 and 3.

The intermediate of formula (Ia) can be prepared by a series ofreactions comprising the reaction of a benzoyl chloride of formula (1)with an acetylene derivative of formula (2) in the presence of a Lewisacid (for example AlCl₃) in a chlorinated solvent, such asdichloromethane. The ketone (3) thus obtained is reduced to the alcohol(4) by reaction with an alkali metal hydride, such as sodiumborohydride, in an alcoholic solvent (for example methanol).Saponification of the ester functional group in the presence of a base,such as sodium or lithium hydroxide, in an alcoholic solvent or in THFthen yields the intermediates of formula (Ia).

The intermediates of formula (Ib) are prepared by oxidation of theintermediate (Ia) in the presence of pyridinium dichromate or manganeseoxide in an organic solvent such as dichloromethane.

The intermediates of formula (Ic) can be prepared by coupling ahalogenated intermediate (4), preferably an iodinated or brominatedcompound, with an α-hydroxyacetylene compound (3) in the presence of apalladium catalyst for example bis(triphenylphosphine)palladium(II)chloride! in a solvent such as triethylamine. The α-hydroxyacetyleneintermediate (3) is prepared by reacting a benzoyl chloride of formula(1) with trimethylsilylacetylene in the presence of a Lewis acid (forexample AlCl₃)in a chlorinated solvent and then reduction of the ketoneobtained (2) with an alkali metal hydride (for example sodiumborohydride) in an alcoholic solvent.

The intermediates of formula (Ic) can also be prepared when R₁ is otherthan --COOR₈ by reacting a lithium phenylacetylide of formula (6) with abenzaldehyde derivative of formula (5) in an organic solvent, such asethyl ether or THF.

The intermediates of formula (Id) can be prepared by reacting a boronacetylide (3) (prepared in situ from lithium phenylacetylide and borontrifluoride at -78° C. in THF) with a tertiary benzamide of formula (4)in an organic solvent such as THF. The compounds of formula (Ie) areprepared by reduction of the preceding compound with an alkali metalhydride.

When R₁ represents a radical --COOH and R₁₀ and R₁₁ together form an oxoradical, the compounds are preferably prepared by protecting R₁ in themethyl, ethyl or allyl ester form, conversion to the free form beingcarried out in the presence of lithium hydroxide in THF.

The present invention also features therapeutic/pharmaceuticalapplications of the compounds of formula (I).

These compounds exhibit activity in the test for differentiation ofmouse embryonic teratocarcinoma cells (F9) (Cancer Research, 43, p. 5268(1983)) and/or in the test for inhibition of ornithine decarboxylaseafter induction with TPA in mice (Cancer Research, 38, p. 793-801(1978)). These tests demonstrate the activities of the subject compoundsfor cell differentiation and proliferation applications, respectively.

The compounds according to the invention are particularly suitable inthe following fields of therapy:

(1) for treating dermatological conditions associated with akeratinization disorder related to differentiation and to proliferation,especially for treating acne vulgaris or comedo-type, polymorphic orrosacea acnes, nodulocystic acne or acne conglobata, senile acnes,secondary acnes such as solar acne, acne medicamentosa or occupationalacne;

(2) for treating other types of keratinization disorders, especiallyichthyoses, ichthyosiform states, Darier's disease, keratoses palmarisand plantaris, leucoplakias and leucoplakia-like states, skin or mucous(buccal) lichen;

(3) for treating other dermatological conditions associated with akeratinization disorder manifesting an inflammatory and/orimmunoallergic component, and, especially, all forms of psoriasis,whether cutaneous, mucous or ungual, and even arthropathic psoriasis,or, alternatively, skin atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds can also be used fortreating inflammatory conditions not exhibiting keratinization disorder;

(4) for treating all dermal or epidermal proliferations, whether benignor malignant, whether or not they are of viral origin, such as verrucavulgaris, verruca plana and epidermodysplasia verruciformis, oral orflorid papillomatoses and proliferations which can be induced byultraviolet radiation, especially in the case of baso- and spinocellularepitheliomas;

(5) for treating other dermatological disorders such as bullousdermatoses and collagen diseases;

(6) for treating certain ophthalmological disorders, especiallycorneopathies;

(7) for repairing or combating skin aging, whether photoinduced orchronologic, or to reduce pigmentations and actinic keratoses, or allpathologies associated with chronologic or actinic aging;

(8) for preventing or curing the stigmas of epidermal and/or dermalatrophy induced by local or systolic corticosteroids, or any other formof skin atrophy;

(9) for preventing or treating cicatrization disorders or for preventingor for repairing vibices;

(10) for combating disorders of the sebaceous function, such as acnehyperseborrhoea or simple seborrhoea;

(11) for the treatment or prevention of cancerous or precancerousstates;

(12) for the treatment of inflammatory conditions such as arthritis;

(13) for the treatment of any condition of viral origin at the level ofthe skin or in general;

(14) for the prevention or treatment of alopecia;

(15) for the treatment of dermatological or general conditions includingan immunological component;

(16) for the treatment of conditions of the cardiovascular system, suchas arteriosclerosis.

For the aforesaid therapeutic or pharmaceutical applications, thecompounds according to the invention can advantageously be used incombination with other compounds displaying retinoid-type activity, withthe D vitamins or derivatives thereof, with corticosteroids, withanti-free radical agents, with α-hydroxy or α-keto acids or derivativesthereof, or alternatively with ion channel blockers. By "D vitamins orderivatives thereof" are intended, for example, the derivatives ofvitamin D₂ or D₃ and in particular 1,25-dihydroxyvitamin D₃. By"anti-free radical agents" are intended, for example, α-tocopherol,superoxide dismutase, ubiquinol or certain metal-chelating agents. By"α-hydroxy or α-keto acids or derivatives thereof" are intended, forexample, lactic, malic, citric, glycolic, mandelic, tartaric, glycericor ascorbic acids or salts, amides or esters thereof. By "ion channelblockers" are intended, for example, minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.

The present invention thus also features medicinal compositionscontaining at least one compound of formula (I), one of its optical orgeometric isomers, or one of its pharmaceutically acceptable salts orother derivatives thereof.

The pharmaceutical/therapeutic compositions of this invention, intendedespecially for the treatment of the aforesaid disease states comprise acarrier which is pharmaceutically acceptable and compatible with themode or regime of administration selected for the given composition, atleast one compound of formula (I), one of its optical or geometricisomers or one of the salts, etc., thereof.

The administration of the compounds according to the invention can becarried out systemically, enterally, parenterally, topically orocularly.

For enteral administration, the medicinal/pharmaceutical compositionsmay be in the form of tablets, gelatin capsules, sugar-coated tablets,syrups, suspensions, solutions, elixirs, powders, granules, emulsions,microopheres or nanospheres or lipid or polymeric vesicles which permita controlled release. For parenteral administration, the compositionsmay be in the form of solutions or suspensions for perfusion or forinjection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight, and this atthe regime or rate of 1 to 3 doses per diem.

For topical administration, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucous membranes and can be providedin the form of ointments, creams, milks, pommades, powders, impregnatedpads, solutions, gels, sprays, lotions or suspensions. They may also beprovided in the form of microopheres or nanospheres or lipid orpolymeric vesicles or polymeric patches and hydrogels which permit acontrolled release.

These compositions for topical administration may, moreover, be providedeither in anhydrous form or in an aqueous form according to theparticular clinical indication.

For ocular administration, they are principally collyria.

These compositions for topical or ocular application contain at leastone compound of formula (I), or one of its optical or geometric isomersor, alternatively, one of its salts, etc., at a concentration preferablyranging from 0.001% to 5% by weight relative to the total weight of thecomposition.

The compounds of formula (I) according to the invention also findapplication in the cosmetic field, in particular for body and hair careand especially for the treatment of skins with acne tendency, for hairregrowth, against loss, for combating the greasy appearance of the skinor the hair, in the protection against the harmful effects of the sun orin the treatment of physiologically dry skins, for preventing and/or forcombating photoinduced or chronologic ageing.

For cosmetic applications, the compositions of the invention may,moreover, be advantageously used in combination with other compoundsdisplaying retinoid-type activity, with the D vitamins or derivativesthereof, with corticosteroids, with anti-free radical agents, withα-hydroxy or α-keto acids or derivatives thereof, or alternatively withion channel blockers, all of these different active agents being asdefined above.

The present invention therefore also features cosmetic compositionscomprising a carrier which is cosmetically acceptable and suitable for atopical application, at least one compound of formula (I) or one of itsoptical or geometric isomers or one of its salts. Such cosmeticcompositions are advantageously presented in the form of a cream, amilk, a lotion, a gel, microspheres or nanospheres or lipid or polymericvesicles, a soap or a shampoo.

The concentration of the compound of formula (I) in the cosmeticcompositions according to the invention advantageously ranges from0.001% to 3% by weight relative to the total composition.

The medicinal and cosmetic compositions according to the invention may,in addition, contain inert or even pharmacodynamically or cosmeticallyactive additives or combinations of these additives, and, especially:wetting agents; depigmenting agents such as hydroquinone, azelaic acid,caffeic acid or kojic acid; emollients; moisturizing agents such asglycerol, PEG 400, thiamorpholinone and its derivatives or alternativelyurea; antiseborrhoeic or antiacne agents such asS-carboxymethylcysteine, S-benzylcysteamine, salts or derivativesthereof, benzoyl peroxide; antibiotics such as erythromycin and estersthereof, neomycin, clindamycin and esters thereof, tetracyclines;antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth,such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) andderivatives thereof, Diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin(5,4-diphenyl-2,4-imidazolidinedione); non-steroidal anti-inflammatoryagents; carotenoids and especially β-carotene; anti-psoriatic agentssuch as anthralin and derivatives thereof; and, lastly,5,8,11,14-eicosatetraynoic and 5,8,11-eicosatrynoic acids and esters andamides thereof.

The compositions according to the invention may also contain taste- orflavor-enhancing agents, preservatives such as parahydroxybenzoic acidesters, stabilizing agents, moisture regulating agents, pH regulatingagents, osmotic pressure modifying agents, emulsifying agents, UV-A andUV-B screening agents, antioxidants such as α-tocopherol, butylatedhydroxyanisole or butylated hydroxytoluene.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 Preparation of methyl 4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of methyl 4-trimethylsilylethynylbenzoate

21.5 g (0.1 mol) of methyl 4-bromobenzoate, 300 ml of triethylamine anda mixture of 200 mg of palladium acetate and of 400 mg oftriphenylphosphine were introduced into a three-necked flask under astream of nitrogen. 20 g (0.204 mol) of trimethylsilylacetylene werethen added, the mixture was heated progressively to 90° C. over 1 hourand maintained at this temperature for 5 hours. The reaction mixture wascooled, the salt filtered and evaporated. The residue was taken up with200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The etherphase was separated by settling, washed with water, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column diluted with dichloromethane. Afterthe evaporation of the solvents, 23 g (100%) of the expected compoundwere recovered in the form of a colorless oil.

(b) Synthesis of methyl 4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)-1-propynyl!benzoate

8.4 g (36 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylchloride, 6.9 g (29.7 mmol) of the above derivative and 100 ml ofdichloromethane were introduced into a round-bottomed flask. 16.8 g (125mmol) of AlCl₃ were added at 0° C. in small amounts and stirring wascarried out at room temperature for 8 hours. The reaction mixture waspoured into ice, extraction was carried out with dichloromethane, andthe organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with a mixture ofdichloromethane and hexane (50/50). 6.8 g (61%) of the expected compoundwere recovered, of melting point 113°-114° C.

EXAMPLE 2 Preparation of methyl4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl/benzoate

4.7 g (125 mmol) of the compound obtained in Example 1(b) and 100 ml ofmethanol were introduced into a round-bottomed flask. 5.7 g (150 mmol)of CeCl₃.7H₂ O and 530 mg (125 mmol) of sodium borohydride were addedsuccessively while cooling at 0° C. and the mixture was stirred at roomtemperature for 4 hours. The reaction mixture was poured into awater/ethyl ether mixture and the organic phase was separated bysettling, washed with water, dried over magnesium sulfate andevaporated. The residue obtained was triturated in 100 ml of hexane,filtered and dried. 4 g (85%) of the expected compound, with a meltingpoint of 142°-143° C., were recovered.

EXAMPLE 3 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

3.5 g (93 mmol) of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,200 ml of methanol and 20 ml of a methanolic sodium hydroxide solution(2N) were introduced into a round-bottomed flask. The reaction mixturewas stirred at room temperature for 8 hours and evaporated and theresidue was taken up in water and acidified with hydrochloric acid.Extraction was carried out with ethyl ether and the organic phase wasseparated by settling, dried over magnesium sulfate and evaporated. Theresidue obtained was recrystallized from a cyclohexane/isopropyl ethermixture and 1.7 g (50% of the expected acid, with a melting point of134°-135° C., was recovered.

EXAMPLE 4 Preparation of 4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid

500 mg (1.38 mmol) of4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, 50 ml of dichloromethane and 2.4 g (27.6 mmol) of manganese oxidewere introduced into a round-bottomed flask which was placed in anultrasonic bath for 4 hours. The reaction mixture was filtered, thefiltrate was evaporated and the residue was purified by simplefiltration through silica in ethyl ether. 90 mg (18%) of the expectedcompound, with a melting point of 208°-209° C., were recovered.

EXAMPLE 5 Preparation of 2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

(a) Preparation of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate

Following the basic procedure of Example 1(a), by reacting 34 g (122mmol) of methyl 2-hydroxy-4-iodobenzoate with 34 ml (244 mmol) oftrimethylsilylacetylene, 25.9 g (85%) of the expected compound wereobtained in the form of a brown oil.

Preparation of methyl 2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 1 (b), by reacting 2.4 g (0.01mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride with2.5 g (0.01 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate,2.9 g (74%) of the expected ester, with a melting point of 189°-190°C.,were recovered.

(c) Synthesis of 2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

1.5 g (3.8 mmol) of the above ester, 100 ml of THF and 485 mg (11.4mmol) of lithium hydroxide monohydrate were introduced into around-bottomed flask. The mixture was heated at reflux for 8 hours, wasevaporated to dryness and the residue was taken up in water andacidified with hydrochloric acid. Extraction was carried out with ethylether and the organic phase was separated by settling, dried overmagnesium sulfate and evaporated. The residue obtained wasrecrystallized from a mixture of cyclohexane and isopropyl ether,filtered and dried. 700 mg (48%) of the expected acid, with a meltingpoint of 183°-184° C., were recovered.

EXAMPLE 6 Preparation of methyl 2-hydroxy -4- 3-hydroxy-3-(5,6,7,8-tetrahydro-5,6,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

2.9 g (7.4 mmol) of methyl 2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoateand 100 ml of a methanol/THF (50/50) mixture were introduced into around-bottomed flask and 140 mg (3.7 mmol) of sodium borohydride wereadded in small amounts. The reaction mixture was stirred at roomtemperature for 2 hours, poured into water and extracted with ethylether. The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with a mixture ofdichloromethane and hexane (50/50). After evaporation of the solvents,1.6 g (55%) of the expected compound, with a melting point of 92°-93°C., was recovered.

EXAMPLE 7 Preparation of 2-hydroxy -4- 3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoic acid

Following the basic procedure of Example 6, from 1 g (2.7 mmol) of2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, 915 mg (91%) of the expected acid, with a melting point of203°-204° C. were recovered.

EXAMPLE 8 Preparation of 2-hydroxy-4-3-oxo-3-(3-tert-butyl-4-methoxyphenyl)1-propynyl!benzoic acid

(a) Preparation of methyl 2-Hydroxy-4-3-oxo-3-(3-tert-butyl-4-methoxyphenyl-1- propynyl!benzoate

Following the basic procedure of Example 1(b), by reacting 4.2 g (0.02mol) of 3-tert-butyl-4-methoxybenzoyl chloride with 5 g (0.02 mol) ofmethyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 6 g (81%) of theexpected compound were obtained, after purification by chromatography ona silica column eluted with dichloromethane, in the form of a brown oil.

(b) Synthesis of 2-hydroxy-4-3-oxo-3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoic acid

Following the basic procedure of Example 5(c), from 6 g (16.4 mmol) ofthe above compound, 4.2 g (73%) of the expected acid, with a meltingpoint of 204°-205° C., were recovered.

EXAMPLE 9 Preparation of 4- 1-oxo-3-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2- propynyl!benzoicacid

(a) Preparation of5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-trimethysilylethynylnaphthalene

Following the basic procedure of Example 1(a), by reacting 26.7 g (0.1mol) of 2-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene with20 g (0.204 mol) of trimethylsilylacetylene, 18.8 g (66%) of theexpected compound were obtained in the form of a colorless oil.

(b) Preparation of5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-ethynylnaphthalene

5.7 g (0.02 mol) of the above compound and 75 ml of methanol wereintroduced into a round-bottomed flask and 100 mg of potassium carbonatewere added. The reaction mixture was stirred at room temperature for 3hours, was evaporated to dryness and the residue was taken up in waterand ethyl ether. The organic phase was separated by settling, dried overmagnesium sulfate and evaporated. 4.1 g (100%) of the expected acetylenewere recovered in the form of a yellow oil.

Preparation of allyl 4-(N,N'-dimethylcarbamoyl)benzoate

20 ml of dimethylamine (40% in water) were introduced into around-bottomed flask and a solution of 2.5 g (11.6 mmol) of4-(allyloxycarbonyl)benzoyl chloride in 50 ml of THF was added dropwise.The reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured into water and extracted with ethyl ether.The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. 2.7 g (100%) of the expected amide wererecovered in the form of a slightly yellow oil.

Preparation of allyl 4-1-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoate

4.3 g (20 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-ethynylnapthalene and 20 ml ofTHF were introduced into a three-necked flask under a stream ofnitrogen. 12.5 ml (20 mmol) of an n-butyllithium solution (1.6M inhexane) were added dropwise at -78° C. and the reaction mixture wasstirred for 10 minutes. 2.7 ml of BF₃ --Et₂ O were then added at thissame temperature and the reaction mixture was stirred for 30 minutes. Asolution of 2.5 g (10 mmol) of allyl 4-(N,N'-dimethylcarbamoyl)benzoatein 10 ml of THF was added, while maintained at -78° C., to the solutionand stirring was carried out for 1 hour. The reaction mixture was pouredinto an aqueous ammonium chloride solution and extraction was carriedout with ethyl ether. The organic phase was separated by settling, driedover magnesium sulfate and evaporated. The residue obtained was purifiedby chromatography on a silica column eluted with a mixture ofdichloromethane and hexane (10/90). After evaporation of the solvents,4.2 g (52%) of the expected ester were recovered in the form of an oil.

(e) Synthesis of 4-1-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid

Following the basic procedure of Example 5(c), from 1.4 g (3.5 mmol) ofthe above ester, 940 mg (75%) of the expected acid, with a melting pointof 191°-192 C., were recovered.

EXAMPLE 10 Preparation of 4-1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoic acid

(a) Preparation of allyl 4-1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoate

Following the basic procedure of Example 6, from 1.7 g (4.2 mmol) ofallyl 4-1-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoate,1.6 g (94%) of the expected ester were obtained in the form of acolorless oil.

(b) Synthesis of4-(1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid

950 mg (2.4 mmol) of the above ester, 50 ml of THF and 75 mg oftetrakis(triphenylphosphine)-palladium(O) were introduced into around-bottomed flask under a stream of nitrogen. 2.1 ml (24 mmol) ofmorpholine were added dropwise at 0° C. and stirring was carried out atambient temperature for 1 hour. The reaction mixture was evaporated andthe residue was taken up in water, acidified to a pH of 1 withhydrochloric acid and extracted with ethyl ether. The organic phase wasseparated by settling, dried over magnesium sulfate and evaporated. Theresidue obtained was triturated in a hexane/ethyl ether (80/20) mixture,filtered and dried. 530 mg (62%) of the expected acid, with a meltingpoint of 161°-162° C., were recovered.

EXAMPLE 11 Preparation of methyl-2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate

(a) Preparation of 4,4-dimethyl-6-thiochromancarboxaldehyde

9.4 g (36.6 mmol) of 4,4-dimethyl-6-bromothiochroman and 100 ml of THFwere introduced into a three-necked flask under a stream of nitrogen.16.1 ml of an n-butyllithium solution (2.5M in hexane) were addeddropwise at -78° C. and stirring was carried out for 30 min. 2.7 ml(38.4 mmol) of DMF were then added dropwise and the mixture waspermitted to heat to room temperature. The reaction mixture was pouredinto an aqueous ammonium chloride solution and extracted with ethylether. The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with a mixture ofdichloromethane and hexane (50/50). After evaporating the solvents, 6.1g (81%) of the expected aldehyde were recovered in the form of a yellowoil.

(b) Preparation ofα-trimethylsilylethynyl-4,4-dimethyl-6-thiochromanmethanol

3 ml (21.3 mmol) of trimethylsilylacetylene and 50 ml of THF wereintroduced into a three-necked flask. A solution of 8.6 ml (21.3 mmol)of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under astream of nitrogen and the reaction mixture was permitted to heat toroom temperature. This solution was introduced dropwise into a solutionof 4 g (19.4 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde in 50 mlof THF at -78° C. The reaction mixture was permitted to heat to roomtemperature, was poured into an aqueous ammonium chloride solution andextracted with ethyl ether. The organic phase was separated by settling,dried over magnesium sulfate and evaporated. 5.9 g (100%) of theexpected alcohol were obtained in the form of a yellow oil.

(c) Preparation of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol

5.9 g (19.4 mmol) ofα-trimethylsilylethynyl-4,4-dimethyl-6-thiochromanmethanol and 50 ml ofTHF were introduced into a round-bottomed flask and 21.3 ml (23.3 mmol)of a tetrabutylammonium fluoride solution (1.1M in THF) were addeddropwise. Stirring was carried out at room temperature for 1 hour andthe reaction mixture was poured into water and extracted with ethylether. The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with a mixture of ethyl acetateand hexane (1/4). After evaporating the solvents, 3.9 g (87%) ofα-ethynyl-4,4-dimethyl-6-thiochromanmethanol were recovered in the formof a colorless oil.

(d) Synthesis of methyl 2-hydroxy-4-3-hydroxy-3F-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate

2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol, 3 g(10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml oftriethylamine were introduced into a three-necked flask. The reactionmixture was degassed with nitrogen for 30 min. and then 600 mg (0.86mmol) of bis(triphenylphosphine)palladium(II) chloride and 240 mg (1.3mmol) of copper iodide were added successively. Stirring was carried outat room temperature for four hours, the reaction mixture was evaporatedto dryness and the residue obtained was taken up in water and ethylether. The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with dichloromethane. 3.2 g(80%) of methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate, with amelting point of 105°-106° C., were recovered.

EXAMPLE 12 Preparation of 2-hydroxy-4-3-oxo-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid

(a) Preparation of methyl 2-hydroxy-4-3-oxo-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate

2 g (5.2 mmol) of methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate and 50 mlof dichloromethane were introduced into a round-bottomed flask. 2.6 g(6.9 mmol) of pyridinium dichromate were added and stirring was carriedout at room temperature for 8 hours. The reaction mixture was evaporatedto dryness and the residue obtained purified by chromatography on asilica column eluted with a mixture of dichloromethane and hexane(50/50). After evaporating the solvents, 1.3 g (65%) of the expectedester was recovered in the form of a brown oil.

(b) Synthesis of 2-hydroxy-4-3-oxo-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid

1.3 g (3.42 mmol) of the above ester, 430 mg (10.2 mmol) of lithiumhydroxide and 50 ml of THF were introduced into a round-bottomed flask.Heating was carried out at reflux for 8 hours and the reaction mixturewas evaporated to dryness. The residue was taken up in water and ethylether and acidified. The organic phase was separated by settling, driedover magnesium sulfate and evaporated. The residue obtained was purifiedby chromatography on a silica column eluted with a mixture ofdichloromethane and-methanol (95/5). 600 mg (48%) of the expected acid,with a melting point of 253°-254° C., were recovered.

EXAMPLE 13 Preparation of 4- 3-hydroxy-3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoic acid

(a) Preparation ofα-trimethylsilylethynyl-3-tert-butyl-4-methoxybenzenemethanol

Following the basic procedure of Example 11(b), by reacting 7.7 g (40mmol) of 3-tert-butyl-4-methoxybenzaldehyde with one equivalent oflithium trimethylsilylacetylide, 11.1 g (98%) of the expected alcoholwere obtained in the form of a colorless oil.

(b) Preparation of α-ethynyl-3-tert-butyl-4-methoxybenzenemethanol

Following the basic procedure of Example 11(c), from 11.1 g (38.2 mmol)of α-trimethylsilylethynyl-3-tert-butyl-4-methoxybenzenemethanol, 8.1 g(96%) of α-ethynyl-3-tert-butyl-4-methoxybenzenemethanol were obtainedin the form of a yellow oil.

(c) Preparation of methyl 4-3-hydroxy-3-(3,tert-butyl-4-methoxyphenyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 2.5 g (11.4mmol) of α-ethynyl-3-tert-butyl-4-methoxybenzenemethanol with 3.17 g(11.4 mmol) of methyl 2-hydroxy-4-iodobenzoate, 3 g (71%) of theexpected ester were obtained in the form of a brown oil.

(d) Synthesis of 4-3-hydroxy-3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoic acid

Following the basic procedure of Example 12(b), from 4.5 g (12.8 mmol)of methyl 4-3-hydroxy-3-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoate, 2.45 g(57%) of the expected acid, with a melting point of 114°-115° C., wererecovered.

EXAMPLE 14 Preparation of methyl N-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate

(a) Preparation ofα-trimethylsilylethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol

17.13 ml (0.121 mol) of trimethylsilylacetylene and 100 ml of THF wereintroduced into a three-necked flask. A solution of 48.5 ml (0.121 mol)of n-butyllithium (2.5M in hexane) was added dropwise at -78° C. under astream of nitrogen and the mixture was permitted to heat to roomtemperature. This solution was introduced dropwise into a solution of23.8 g (0.11 mol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde in100 ml of THF at -78° C. The reaction mixture was permitted to heat toroom temperature, was poured into an aqueous ammonium chloride solutionand was extracted with ethyl ether. The organic phase was separated bysettling, dried over magnesium sulfate and evaporated. The residueobtained was purified by chromatography on a silica column eluted with amixture of dichloromethane and hexane (50/50). After evaporating thesolvents, 29.9 g (86%) of the expected alcohol were recovered in theform of a yellow oil.

(b) Preparation ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol

29.9 g (92.5 mmol) ofα-trimethyl-silylethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanoland 100 ml of THF were introduced into a round-bottomed flask and 103.8ml (114.2 mmol) of a tetrabutylammonium fluoride solution (1.1M in THF)were added dropwise. Stirring was carried out at room temperature forone hour and the reaction mixture was poured into water and extractedwith ethyl ether. The organic phase was separated by settling, driedover magnesium sulfate and evaporated. The residue obtained was purifiedby chromatography on a silica column eluted with a mixture of ethylacetate and hexane (1/4). After evaporating the solvents, 18.1 g (79%)ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,with a melting point of 56°-57° C., were recovered.

(c) Preparation of 2-trichloroacetylpyrrole

45 g (247 mmol) of trichloroacetyl chloride and 100 ml of ethyl etherwere introduced into a three-necked flask. A solution of 15.4 g (230mmol) of pyrrole in 100 ml of ethyl ether was added dropwise andstirring was carried out at room temperature for one hour. A solution of20 g of potassium carbonate in 60 ml of water was then slowly added. Theorganic phase was separated by settling, dried over magnesium sulfateand evaporated and the residue was triturated in hexane and filtered.42.7 g (87%) of the expected compound, with a melting point of 78°-79°C., were recovered.

(d) Preparation of 4-iodo-2-trichloroacetylpyrrole

8.4 g (39.5 mmol) of 2-trichloroacetylpyrrole and 100 ml of chloroformwere introduced into a three-necked flask under a stream of nitrogen and8.8 g (39.5 mmol) of silver trifluoroacetate and 10.16 g (39.5 mmol) ofiodine were added successively. Stirring was carried out at roomtemperature for one hour and the reaction mixture was poured into iceand extracted with dichloromethane. The organic phase was separated bysettling, dried over magnesium sulfate and evaporated. The residueobtained was triturated in hexane and filtered. 8.2 g (61%) of theexpected compound, with a melting point of 118°-119° C., were recovered.

(e) Preparation of methyl 4-iodo-2-pyrrolecarboxylate

8.2 g (24 mmol) of 4-iodo-2-trichloroacetylpyrrole and 100 ml ofmethanol were introduced into a round-bottomed flask and 2 g (36 mmol)of sodium methoxide were added. Stirring was carried out at roomtemperature for four hours, the reaction mixture was evaporated todryness and the residue obtained was taken up in water and ethyl ether.The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was triturated in heptaneand filtered. 4.9 g (81%) of the expected ester, with a melting point of77°-78° C., were recovered.

(f) Preparation of methyl N-methyl-4-iodo-2-pyrrolecarboxylate

780 mg (25.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF wereintroduced into a three-necked flask, a solution of 6.5 g (25.9 mmol) ofmethyl 4-iodo-2-pyrrolecarboxylate in 50 ml of DMF was added dropwiseand stirring was carried out until gas evolution has ceased. 2.1 ml(33.6 mmol) of iodomethane were then added and stirring was carried outat room temperature for two hours. The reaction mixture was poured intowater and extracted with ethyl ether. The organic phase was separated bysettling, dried over magnesium sulfate and was evaporated. The residueobtained was purified by chromatography on a silica column eluted with amixture of dichloromethane and hexane (40/60). 4.5 g (65%) of methylN-methyl-4-iodo-2-pyrrolecarboxylate, with a melting point of 64°-65°C., were recovered.

(g) Synthesis of methyl N-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate

Following the basic procedure of Example 11(d), by reacting 2.9 g (12mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 3.2 g (12.1 mmol) of methyl N-methyl-4-iodo-2-pyrrolecarboxylate,2.8 g (61%) of the expected ester, with a melting point of 150°-152° C.,were recovered by trituration in isopropyl ether.

EXAMPLE 15 Preparation of N-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylicacid

Following the basic procedure of Example 12(b), from 2 g (5.2 mmol) ofmethyl N-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate,440 mg (22% of the expected acid, with a melting point of 112°-113° C.,were recovered.

EXAMPLE 16 Preparation of methyl-4-3-hydroxy-3-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate

(a) Preparation of methylN-tert-butoxycarbonyl-4-iodo-2-pyrrolecarboxylate

780 mg (25.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF wereintroduced into a three-necked flask, a solution of 6.5 g (25.9 mmol) ofmethyl 4-iodo-2-pyrrolyecarboxylate in 50 ml of DMF was added dropwiseand stirring was carried out until gas evolution has ceased. 5.6 g (25.9mmol) of di-tert-butyl dicarbonate were then added in small amounts andstirring was carried out at room temperature for two hours. The reactionmixture was poured into water and extracted with ethyl ether. Theorganic phase was separated by settling, dried over magnesium sulfateand evaporated. The residue obtained was purified by chromatography on asilica column eluted with a mixture of dichloromethane and hexane(60/40). 6.8 g (75%) of methylN-tert-butoxycarbonyl-4-iodo-2-pyrrolecarboxylate were recovered in theform of a yellow oil.

(b) Preparation of methyl N-tert-butoxycarbonyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate

Following the basic procedure of Example 11(d), by reacting 2 g (8.2mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 3 g (8.5 mmol) of methylN-tert-butoxycarbonyl-4-iodo-2-pyrrolecarboxylate, 3.8 g (98%) of theexpected ester were obtained in the form of a brown oil.

(c) Synthesis of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-pyrrolecarboxylate

2.4 g (5.1 mmol) of the above ester, 20 ml of THF and 20 ml of methanolwere introduced into a round-bottomed flask. 278 mg (5.1 mmol) of sodiummethoxide were added and stirring was carried out at room temperaturefor four hours. The reaction mixture was evaporated to dryness and theresidue was taken up in water and ethyl ether. The organic phase wasseparated by settling, dried over magnesium sulfate and evaporated. Theresidue obtained was triturated in a mixture of diisopropyl ether andheptane and filtered. 1.22 g (65%) of the expected ester, with a meltingpoint of 95°-100° C., was recovered.

EXAMPLE 17 Preparation of methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate

(a) Preparation of 4,4-dimethyl-7-thiochromancarboxaldehyde

Following the basic procedure of Example 11(a), from 5.6 g (21.8 mmol)of 4,4-dimethyl-7-bromothiochroman, 3.3 g (74%) of the expected aldehydewere obtained in the form of a yellow oil.

(b) Preparation ofα-trimethylsilylethynyl-4,4-dimethyl-7-thiochromanmethanol

Following the basic procedure of Example 11(b), from 5.4 g (26.2 mmol)of 4,4-dimethyl-7-thiochromancarboxaldehyde, 8 g (100%) ofα-trimethylsilylethynyl-4,4-dimethyl-7-thiochromanmethanol were obtainedin the form of a yellow oil.

(c) Preparation of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol

Following the basic procedure of Example 11(c), from 8 g (26.3 mmol) ofα-trimethylsilylethynyl-4,4-dimethyl-7-thiochromaranethanol, 4.3 g (70%)of the expected alcohol, after purification, were obtained in the formof a colorless oil.

(d) Synthesis of methyl2-hydroxy-4-(3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate

2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol, 3 g(10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml oftriethylamine were introduced into a three-necked flask. The reactionmixture was degassed with nitrogen for 30 min. and then 600 mg (0.86mmol) of bis(triphenylphosphine)palladium(II) chloride and 240 mg (1.3mmol) of copper iodide were successively added. Stirring was carried outat room temperature for four hours and the reaction mixture wasevaporated to dryness and the residue obtained taken up in water andethyl ether. The organic phase was separated by settling, dried overmagnesium sulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with dichloromethane. 3.2 g(80%) of methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate, with amelting point of 101°-102° C., were recovered.

EXAMPLE 18 Preparation of 4-1-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-2-propynyl!benzoic acid

(a) Preparation of 2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl)ethylene

5 g (24.2 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde, prepared inExample 11(a), and 50 ml of dichloromethane were introduced into around-bottomed flask. 16.1 g (48.4 mmol) of carbon tetrabromide, 12.7 g(48.4 mmol) of triphenylphosphine and 3.16 g (48.4 mmol) of zinc powderwere successively added and stirring was carried out at room temperaturefor two hours. The reaction mixture was evaporated and the residueobtained purified by chromatography on a silica column eluted withhexane. 7.75 g (88%) of the expected compound were recovered.

(b) Preparation of (4,4-dimethylthiochroman-6-yl)acetylene

7.7 g (21.2 mmol) of2,2-dibromo-1-(4,4-dimethylthiochroman-6-yl)ethylene and 80 ml of THFwere introduced into a three-necked flask under a stream of nitrogen. 17ml (26.6 mmol) of an n-butyllithium solution (2.5M in hexane) were addeddropwise at -78° C. and the mixture was permitted to heat to roomtemperature for one hour. The reaction mixture was poured into water andextracted with ethyl ether. The organic phase was separated by settling,dried over magnesium sulfate and evaporated. The residue obtained waspurified by chromatography on a silica column eluted with heptane. 3.9 g(90%) of the expected acetylene derivative were recovered in the form ofa yellow oil.

(c) Synthesis of 4-1-hydroxy-3-4,4-dimethylthiochroman-6-yl)-2-propynyl!benzoic acid

2 g (9.9 mmol) of (4,4-dimethylthiochroman-6- yl)acetylene and 25 ml ofTHF were introduced into a three-necked flask under a stream ofnitrogen, 4 ml (9.9 mmol) of an n-butyllithium solution (2.5M in hexane)were added dropwise at -50° C. and stirring was carried out for 30 min.A solution of 743 mg (4.9 mmol) of 4-carboxybenzaldehyde in 25 ml of THFwas then added and stirring was carried out at room temperature for onehour. The reaction mixture was poured into water and extracted withethyl ether. The organic phase was separated by settling, dried overmagnesium sulfate and evaporated. The residue was recrystallized fromdiisopropyl ether. After filtration, 730 mg (42%) of the expected acid,with a melting point of 168°-169° C., were obtained.

EXAMPLE 19 Preparation of 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid

Following the basic procedure of Example 12(b), from 2 g (5.2 mmol) ofmethyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6yl)-1-propynyl!benzoate, 1.66 g(86%) of the expected acid, with a melting point of 240°-245° C., wasobtained.

EXAMPLE 20 Preparation of 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoic acid

Following the basic procedure of Example 12(b), from 2 g (5.2 mmol) ofmethyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate, 1.55 g(80%) of the expected acid, with a melting point of 144°-145° C., wasobtained.

EXAMPLE 21 Preparation of (+)-isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of (-)-diastereoisomer of1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl(R)-α-methoxyphenylacetate

9.7 g (40 mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,6.7 g (40 mmol) of (R)-(-)-α-methoxyphenylacetic acid and 100 ml ofdichloromethane were introduced into a round-bottomed flask. 8.3 g (40mmol) of dicyclohexylcarbodiimide and 4.9 g (40 mmol) of4-dimethylaminopyridine were successively added and stirring was carriedout at room temperature for 24 hours. The reaction mixture was pouredinto water and extracted with ethyl ether. The organic phase wasseparated by settling, dried over magnesium sulfate and evaporated. Theresidue obtained was purified by chromatography on a silica columneluted with a mixture of dichloromethane and heptane (60/40). Afterevaporating the solvents, 3.8 g (97%) of the mixture of diastereoisomerswere recovered the form of an oil.

Separation of the two diastereoisomers was carried out by two successiverecrystallizations from isooctane. 6 g (38.4%) of the(-)-diastereoisomer, with a melting point of 94°-95° C., were thusobtained.

α!_(D) ²⁰ =-14°8 (C=1, CH₂ Cl₂)

(b) Preparation of (-)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol

5.7 g (14.6 mmol) of the (-)-diastereoisomer prepared above and 20 ml ofTHF were introduced into a round-bottomed flask and 10 ml of amethanolic sodium hydroxide solution (2N) were added. Stirring wascarried out at room temperature for one hour and the reaction mixturewas evaporated to dryness and taken up in water and ethyl ether. Theorganic phase was separated by settling, dried over magnesium sulfateand evaporated. The residue obtained was purified by chromatography on asilica column eluted with dichloromethane. After evaporating thesolvents, 3.4 g (97%) of the (-)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,with a melting point of 77°-78° C., were recovered.

α!_(D) ²⁰ =-20°7 (c=1, CH₂ Cl₂)

(c) Synthesis of (+)-isomer of methyl4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.6 g (6.6mmol) of the (-)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.7 g (6.6 mmol) of methyl 4-iodobenzoate, there were obtained,after chromatography on a silica column eluted with a mixture ofdichloromethane and heptane (60/40), 2.1 g (84.6%) of the (+)-isomer ofmethyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,with a melting point of 128°-129° C.

α!_(D) ²⁰ =+18°6 (c=1, CH₂ Cl₂)

EXAMPLE 22 Preparation of (-)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 1.6 g of the(+)-isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,1.1 g (73%) of the (-)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, with a melting point of 183°-184° C., was obtained.

α!_(D) ²⁰ =-1.1° (c=1, DMF)

EXAMPLE 23 Preparation of (+)-isomer of methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.5 g (6.2mmol) of the (-)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.7 g (6.2 mmol) of methyl 2-hydroxy-4-iodobenzoate, there wereobtained, after chromatography on a silica column eluted with a mixtureof dichloromethane and heptane (70/30), 2.2 g (91%) of the (+)-isomer ofmethyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,with a melting point of 100°-101° C.

α!_(D) ²⁰ =+17°9 (c=1, CH₂ Cl₂)

EXAMPLE 24 Preparation of (-)-isomer of 2-hydroxy-4-3-hydroxy-4-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid:

Following the basic procedure of Example 12(b), from 1.8 g of the(+)-isomer of methyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,1.5 g (88%) of the (-)-isomer of 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid, with a melting point of 220° C. with decomposition, was obtained.

α!_(D) ²⁰ =-1° (c=1, DMF)

EXAMPLE 25 Preparation of (-)-isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of (+)-diastereoisomer of1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl(S)-α-methoxyphenylacetate

9.3 g (38.4 mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,6.4 g (38.4 mmol) of (S)-(+)-α-methoxyphenylacetic acid and 100 ml ofdichloromethane were introduced into a round-bottomed flask. 7.9 g (38.4mmol) of dicyclohexylcarbodiimide and 4.7 g (38.4 mmol) of4-dimethylaminopyridine were successively added and stirring was carriedout at room temperature for 24 hours. The reaction mixture was pouredinto water and extracted with ethyl ether. The organic phase wasseparated by settling, dried over magnesium sulfate and evaporated. Theresidue obtained was purified by chromatography on a silica columneluted with a mixture of dichloromethane and heptane (60/40). Afterevaporating the solvents, 12.5 g (84%) of the mixture ofdiastereoisomers were recovered in the form of an oil.

Separation of the two diastereoisomers was carried out by two successiverecrystallizations from isooctane. 4 g (27%) of the (+)-diastereoisomer,with a melting point of 93°-94° C., were thus obtained.

α!_(D) ²⁰ =+16°9 (c=1, CH₂ Cl₂)

(b) Preparation of (+)-isomer ofα-ethynyl-5,5,6,7,8-tetrahydro-5,8,8-tetramethyl-2-naphthalenemethanol

3.7 g (9.5 mmol) of the (+)-diastereoisomer prepared above and 20 ml ofTHF were introduced into a round-bottomed flask and 10 ml of amethanolic sodium hydroxide solution (2N) were added. Stirring wascarried out at room temperature for one hour and the reaction mixturewas evaporated to dryness and taken up in water and ethyl ether. Theorganic phase was separated by settling, dried over magnesium sulfateand evaporated. The residue obtained was purified by chromatography on asilica column eluted with dichloromethane. After evaporating thesolvents, 1 g (87%) of the (+)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,with a melting point of 77°-78° C., was recovered.

α!_(D) ²⁰ =+18°7 (c=1, CH₂ Cl₂)

(c) Synthesis of (-)-isomer of methyl 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 700 mg (2.9mmol) of the (+)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 760 mg (2.9 mmol) of methyl 4-iodobenzoate, there was obtained,after chromatography on a silica column eluted with a mixture ofdichloromethane and heptane (60/40), 1 g (92.5%) of the (-)-isomer ofmethyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,with a melting point of 128°-129° C.

α!_(D) ²⁰ =-18°1 (c=1, CH₂ Cl₂)

EXAMPLE 26 Preparation of (-)-isomer of methyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1 g (4.1mmol) of the (+)-isomer ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.1 g (4.1 mmol) of methyl 2-hydroxy-4-iodobenzoate, there wasobtained, after chromatography on a silica column eluted with a mixtureof dichloromethane and heptane (70/30), 1.45 g (90%) of the (-)-isomerof methyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,with a melting point of 100°-101° C.

α!_(D) ²⁰ =-17°6 (c=1, CH₂ Cl₂)

EXAMPLE 27 Preparation of (+)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 800 mg of the(-)-isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,600 mg (78%) of the (+)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, with a melting point of 180°-181° C., were obtained.

α!_(D) ²⁰ =+1.1° (c=1, DMF)

EXAMPLE 28 Preparation of (+)-isomer of 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 1.2 g of the(-)-isomer of methyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoate,1 g (87%) of the (+)-isomer of2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, with a melting point of 220° C. with decomposition, was obtained.

α!_(D) ²⁰ =+1° (C=1, DMF)

EXAMPLE 29 Preparation of methyl 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of1-trimethylsilylethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol

Following the basic procedure of Example 11(b), by reacting 5 g (21.7mmol) of 2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene withone equivalent of lithium trimethylsilylacetylide, 6.8 g (95%) of theexpected alcohol were obtained in the form of a colorless oil.

(b) Preparation of1-ethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol

Following the basic procedure of Example 11(c), from 6.8 g (20.7 mmol)of1-trimethylsilylethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol,4.22 g (75%) of the expected compound, with a melting point of 84°-85°C., were obtained.

(c) Synthesis of methyl 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 2 g (7.8mmol) of1-ethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanolwith 2.2 g (7.9 mmol) of methyl 2-hydroxy-4-iodobenzoate, there wereobtained, after chromatography on a silica column eluted with a mixtureof dichloromethane and heptane (50/50), 2.77 g (87%) of the expectedester, with a melting point of 110°-115° C.

EXAMPLE 30 Preparation of 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 2.2 g (5.4 mmol) ofmethyl 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,1.9 g (89%) of the expected acid, with a melting point of 265°-270° C.,was obtained.

EXAMPLE 31 Preparation of 2-Methoxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

(a) Preparation of methyl 4-iodo-2-methoxybenzoate

238 mg (7.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF wereintroduced into a three-necked flask, a solution of 2 g (7.2 mmol) ofmethyl 2-hydroxy-4-iodobenzoate in 50 ml of DMF was added dropwise andstirring was carried out until gas evolution had ceased. 540 μl (8.6mmol) of iodomethane were then added and stirring was carried out atroom temperature for two hours. The reaction mixture was poured intowater and extracted with ethyl ether. The organic phase was separated bysettling, dried over magnesium sulfate and evaporated. 2.1 g (100%) ofmethyl 4-iodo-2-methoxybenzoate were recovered.

(b) Preparation of methyl 2-methoxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.66 g (6.8mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 2 g (6.9 mmol) of methyl 4-iodo-2-methoxybenzoate, 2.1 g (75%) ofthe expected ester were obtained, after chromatography on a silicacolumn eluted with dichloromethane, in the form of a yellow oil.

(c) Synthesis of 2-methoxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 2.1 g (5.2 mmol) ofthe above ester, 1 g (50%) of the expected acid, with a melting point of100°-102° C., was obtained.

EXAMPLE 32 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzaldehyde

2.42 g (10 mmol) of-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol, 2g (11 mmol) of 4-bromobenzaldehyde and 50 ml of triethylamine wereintroduced into a three-necked flask. The reaction mixture was degassedwith nitrogen for 30 min. and then 169 mg (0.75 mmol) of palladium(II)acetate and 393 mg (1.5 mmol) of triphenylphosphine were successivelyadded. Heating was carried out at 60° C. for one hour, the reactionmixture was evaporated to dryness and the residue obtained was taken upin water and ethyl ether. The organic phase was separated by settling,dried over magnesium sulfate and evaporated. The residue obtained waspurified by chromatography on a silica column eluted with a mixture ofdichloromethane and heptane (70/30). 1.23 g (35.5%) of4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzaldehyde,with a melting point of 104°-105° C., was recovered.

EXAMPLE 33 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzylacetate

Following the basic procedure of Example 32, by reacting 2.42 g (10mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 2.52 g (11 mmol) of 4-bromobenzyl acetate, 790 mg (20%) of theexpected compound were obtained in the form of a brown oil.

EXAMPLE 34 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzenemethanol

780 mg (2 mmol) of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzylacetate and 30 ml of THF were introduced into a round-bottomed flask. 5ml of a 2N methanolic sodium hydroxide solution were added and stirringwas carried out for 30 min. The reaction mixture was poured into waterand extracted with ethyl ether. The organic phase was separated bysettling, dried over magnesium sulfate and evaporated. The residueobtained was triturated in heptane and filtered, 419 mg (60%) of theexpected compound, with a melting point of 85°-86° C., were recovered.

EXAMPLE 35 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!toluene

Following the basic procedure of Example 11(d), by reacting 1.2 g (5mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.1 g (5 mmol) of 4-iodotoluene, 1.49 g (45%) of the expectedcompound was recovered, after chromatography on a silica column elutedwith dichloromethane, in the form of a brown oil.

EXAMPLE 36 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1propynyl!phenylacetate

(a) Preparation of 2-bromo-5,67,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene

30 ml of 2-bromotoluene and 14 g (0.11 mol) of AlCl₃ were introducedinto a three-necked flask, cooling was carried out to 0° C. and asolution of 50 g (0.27 mol) of 2,5-dichloro-2,5-dimethylhexane in 100 mlof 2-bromotoluene was added dropwise, and the reaction mixture waspermitted to heat to room temperature. The reaction mixture was pouredinto water and extracted with dichloromethane. The organic phase wasseparated by settling, washed with an aqueous sodium bicarbonatesolution and evaporated. The product crystallized on stirring inmethanol. After filtration, 56.9 g (75%) of2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene, with amelting-point of 92°-93° C., were recovered.

(b) Preparation of5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenecarboxaldehyde

Following the basic procedure of Example 11(a), from 8.44 g (30 mmol) of2-bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene, 6.9 g(100%) of the expected aldehyde, with a melting point of 75°-76° C.,were obtained.

(c) Preparation ofα-trimethylsilylethynyl-5,6,7,8-tetrahydro-3,5,5,8-pentamethyl-2-naphthalenemethanol

Following the basic procedure of Example 11(b), by reacting 6.66 g (29mmol) of5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenecarboxaldehydewith one equivalent of lithium trimethylsilylacetylide, 8.8 g (92%) ofthe expected alcohol, with a melting point of 95°-96° C., were obtained.

(d) Preparation ofα-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol

Following the basic procedure of Example 11(c), from 8.6 g (26 mmol) ofα-trimethylsilylethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol,4.8 g (72%) of the expected compound, with a melting point of 101°-102°C., were obtained.

(e) Synthesis of 4- 3-hydroxy-3-(5,6,78-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!phenyl acetate

Following the basic procedure of Example 11(d), by reacting 1.28 g (5mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol with 1.44g (5.5 mmol) of 4-iodophenyl acetate, 480 mg (25%) of the expectedcompound, with a melting point of 129°-130° C., were obtained.

EXAMPLE 37 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!phenol

Following the basic procedure of Example 34, from 300 mg (0.77 mmol) )of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl-1-propynyl!phenylacetate, 207 mg (77%) of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!phenol,with a melting point of 158°-159° C., were obtained.

EXAMPLE 38 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!phenylsulfinylmethane

(a) Preparation of 4-bromophenylsulfinylmethane

4.06 g (20 mmol) of 4-bromothioanisole and 75 ml of dichloromethane wereintroduced into a round-bottomed flask and 6.3 g (20 mmol) ofmeta-chloroperbenzoic acid were added. Stirring was carried out at roomtemperature for four hours and the reaction mixture was poured intowater. The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with a mixture ofdichloromethane and heptane (70/30). After evaporating the solvents,1.22 g (28%) of the expected sulfoxide, with a melting point of 80°-81°C., was recovered.

(b) Synthesis of4-3-hydroxy-3-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl2-naphthyl)-1-propynyl)phenylsulfinylmethane

Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol)ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.1 g (5 mmol) of 4-bromophenylsulfinylmethane, 177 mg (9%) of theexpected sulfoxide compound, with a melting point of 121°-122° C., wereobtained.

EXAMPLE 39 Preparation of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfonylmethane

Preparation of 4-bromophenylsulfonylmethane

Following the basic procedure of Example 38(a), by reacting 2.03 g (10mmol) of 4-bromothioanisole with 10.35 g (30 mmol) ofmetachloroperbenzoic acid, 1.72 g (73%) of the expected sulfone, with amelting point of 94°-95° C., was obtained.

Synthesis of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfonylmethane

Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol)ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.18 g (5 mmol) of 4-bromophenylsulfonylmethane, 610 mg (31%) ofthe expected sulfone compound, with a melting point of 112°-113° C.,were obtained.

EXAMPLE 40 Preparation of N-ethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide

(a) Preparation of 4-iodobenzol chloride

5 g (20 mmol) of 4-iodobenzoic acid, 30 ml of toluene and 5 drops of DMFwere introduced into a round-bottomed flask. Heating was carried out to40° C., 1.74 ml (24 mmol) of thionyl chloride was added and stirring wascarried out for 30 minutes. Evaporation was carried out to dryness and5.5 g (100%) of the crude acid chloride were recovered, which compoundwas employed as is in the continuation of the synthesis.

(b) Preparation of N-ethyl-4-iodobenzamide

90 ml (45 mmol) of a 0.5N solution of ethylamine in THF were introducedinto a round-bottomed flask and a solution of 4 g (15 mmol) of4-iodobenzoyl chloride in 20 ml of dichloromethane was added dropwise.Stirring was carried out at room temperature for one hour and thereaction mixture was poured into water and extracted with ethyl ether.The organic phase was separated by settling, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column eluted with dichloromethane. Afterevaporating the solvents, 3.41 g (82%) of the expected amide wererecovered.

Synthesis ofN-ethyl-4-(3-hydroxy-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide

Following the basic procedure of Example 11(d), by reacting 1.21 g (5mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.37 g (5.1 mmol) of N-ethyl-4-iodobenzamide, 596 mg (31%) of theexpected amide, with a melting point of 153°-154° C., were obtained.

EXAMPLE 41 Preparation of N,N'-diethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide

(a) Preparation of N,N'-diethyl-4-iodobenzamide

Following the basic procedure of Example 40(b), by reacting 5 g (18mmol) of 4-iodobenzoyl chloride with 5.6 ml (54 mmol) of diethylamine,3.4 g (62%) of the expected amide were obtained.

(b) Synthesis of N,N'-diethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl)benzamide

Following the basic procedure of Example 11(d), by reacting 970 mg (4mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.25 g (4.1 mmol) of N,N'-diethyl-4-iodobenzamide, 584 mg (35%) ofthe expected amide were obtained in the form of a brown oil.

EXAMPLE 42 Preparation of morpholide of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid

(a) Preparation of morpholide of 4-iodobenzoic acid

Following the basic procedure of Example 40(b), by reacting 4 g (15mmol) of 4-iodobenzoyl chloride with 3.9 ml (45 mmol) of morpholine,3.64 g (76 of the expected amide were obtained.

(b) Synthesis of morpholide of 4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1propynyl!benzoicacid

Following the basic procedure of Example 11(d), by reacting 1.21 g (5mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.62 g (5.1 mmol) of the morpholide of 4-iodobenzoic acid, 423 mg(20%) of the expected amide, with a melting point of 122°-123° C., wereobtained.

EXAMPLE 43 Preparation of methyl 5-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-2-thiophenecarboxylate

Following the basic procedure of Example 32, by reacting 1.21 g (5 mmol)) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g(5 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 371 mg (19%) of theexpected methyl ester, with a melting point of 84°-85° C., wereobtained.

EXAMPLE 44 Preparation of methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.28 g (5mmol) ofα-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanolprepared in Example 37(d)! with 1.5 g (5.5 mmol) of methyl2-hydroxy-4-iodobenzoate, 739 mg (36%) of the expected compound, with amelting point of 112°-113° C., were obtained.

EXAMPLE 45 Preparation of 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 600 mg (1.5 mmol)of methyl2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoate,132 mg (23%) of the expected acid, with a melting point of 88°-89° C.,were obtained.

EXAMPLE 46 Preparation of methyl 2-hydroxy-4--3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of2-bromo-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene

36.6 g (0.2 mol) of 2,5-dichloro-2,5-dimethylhexane, 34.6 g (0.2 mol) of2-bromophenol and 400 ml of dichloromethane were introduced successivelyinto a three-necked flask. 26.6 g (0.2 mol) of AlCl₃ were added in smallamounts at 0° C. and stirring was carried out until gas evolution hadceased (violent reaction). The reaction mixture was poured into waterand the organic phase was separated by settling, washed with an aqueoussodium bicarbonate solution, dried over magnesium sulfate andevaporated. The residue was purified by chromatography on a silicacolumn eluted with a mixture of ethyl acetate and heptane (10/90). Afterevaporating the solvents, 20.6 g (36%) of the expected phenol wererecovered.

(b) Preparation of2-bromo-3-methoxy-5,5,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene

720 mg (24 mmol) of sodium hydride (80% in oil) and 20 ml of DMF wereintroduced into a three-necked flask, a solution of 5.7 g (20 mmol) of2-bromo-3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in75 ml of DMF was added dropwise and stirring was carried out until gasevolution had ceased. 1.5 ml (24 mmol) of iodomethane was then added andstirring was carried out at room temperature for two hours. The reactionmixture was poured into water and extracted with ethyl ether. Theorganic phase was separated by settling, dried over magnesium sulfateand evaporated. The residue obtained was triturated in heptane andfiltered. 5.5 g (93%) of2-bromo-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene,with a melting point of 70°-71° C., were recovered.

(c)) Preparation of3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehyde

Following the basic procedure of Example 11(a), from 5.3 g (17.8 mmol)of 2-bromo-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene,3.5 g (80%) of the expected aldehyde, with a melting point of 125°-126°C., were obtained.

(d) Preparation ofα-trimethylsilylethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol

Following the basic procedure of Example 11(b), by reacting 3.21 g (13mmol) of3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenecarboxaldehydewith one equivalent of lithium trimethylsilylacetylide, 4.4 g (99%) ofthe expected alcohol were obtained in the form of a yellow oil.

(e) Preparation ofα-ethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8--tetramethyl-2-naphthalenemethanol

Following the basic procedure of Example 11(c), from 4.4 g (12.7 mmol)ofα-trimethylsilylethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol,1.15 g (33%) of the expected compound was obtained.

(f) Synthesis of methyl 2-hydroxy-4-3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.15 g (4.2mmol) ofα-ethynyl-3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.21 g (4.64 mmol) of methyl 2-hydroxy-4-iodobenzoate, 1.36 g (76%)of the expected product, with a melting point of 125°-126° C., wereobtained.

EXAMPLE 47 Preparation of 2-hydroxy-4-3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 1.1 g (2.6 mmol) ofmethyl 2-hydroxy-4-3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1propynyl!benzoate,890 mg (84% of the expected acid, with a melting point of 225°-228° C.,were obtained.

EXAMPLE 48 Preparation of 4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid

(a) Preparation of methyl 4-3-Hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 1.4 g (6mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol with 1.6 g (6mmol) of methyl 4-iodobenzoate, 1.5 g (68%) of the expected ester wasobtained in the form of an orange-colored oil.

(b) Synthesis of 4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid

Following the basic procedure of Example 12(b), from 1 g (2.7 mmol) ofmethyl 4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate, 450 mg(47%) of the expected acid, with a melting point of 147°-149° C., wereobtained.

EXAMPLE 49 Preparation of 4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1propynyl!benzoic acid

(a) Preparation of methyl 4-3-Hydroxy-3-(4,4-dimethylthiochroman-7yl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 2 g (8.6mmol) of α-ethynyl-4,4- dimethyl-7-thiochromanmethanol with 2.25 g (8.6mmol) of methyl 4-iodobenzoate, 1.8 g (57%) of the expected ester wasobtained in the form of an yellow oil.

(b) Synthesis of 4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoic acid

Following the basic procedure of Example 12(b), from 1.2 g (3.3 mmol) ofmethyl 4-3-Hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate, 300 mg(26%) of the expected acid, with a melting point of 151°-153° C., wereobtained.

EXAMPLE 50 Preparation of methyl 3-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

(a) Preparation of 3-methyl-4-iodobenzoic acid

20 g (0.132 mol) of 3-methyl-4-aminobenzoic acid and 175 ml of sulfuricacid (20%) were introduced into a three-necked flask. A solution of 11.9g (0.172 mol) of sodium nitrite in 50 ml of water was added dropwise at-10° C. and stirring was carried out for two hours. This solution wasintroduced dropwise via a refrigerated dropping funnel at -50° C. into asolution of 35 g (0.211 mol) of potassium iodide, 35.2 g (0.185 mol) ofcopper iodide and 175 ml of sulfuric acid (20%). Stirring was carriedout for eight hours, the reaction mixture was filtered and the solidobtained was dissolved in ethyl acetate. Washing was carried out withwater and then with a sodium sulfite solution, drying was carried outover magnesium sulfate and evaporation was carried out. 24.4 g (70%) of3-methyl-4-iodobenzoic acid, with a melting point of 205°-210° C., wererecovered.

(b) Preparation of methyl 3methyl-4-iodobenzoate

24.4 g (0.093 mol) of 3-methyl-4-iodobenzoic acid and 250 ml of methanolwere introduced into a round-bottomed flask and 2.5 ml of concentratedsulfuric acid were added dropwise. Heating was carried out at reflux fortwelve hours, the reaction mixture was evaporated and the residue takenup in ethyl acetate and water. The organic phase was separated bysettling, dried over magnesium sulfate and evaporated. The residue wastriturated in methanol and filtered. 21.9 g (85%) of the expected methylester, with a melting point of 58°-59° C., were recovered.

(c) Synthesis of methyl 3-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 2.4 g (10mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 2.7 g (10 mmol) of methyl 3-methyl-4-iodobenzoate, 3.2 g (83%) ofthe expected ester, with a melting point of 130°-131° C., were obtained.

EXAMPLE 51 Preparation of 3-Methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(d), from 2.2 g (5.6 mmol) ofmethyl3-methyl-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,1.5 g (71%) of3-methyl-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, with a melting point of 189°-190° C., was obtained.

EXAMPLE 52 Preparation of 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

(a) Preparation of 2-chloro-4-iodobenzoic acid

Following the basic procedure of Example 50(a), from 10 g (58.3 mmol) of2-chloro-4-aminobenzoic acid, 14.26 g (86%) of 2-chloro-4-iodobenzoicacid were recovered.

(b) Preparation of methyl 2-chloro-4-iodobenzoate

Following the basic procedure of Example 50(b), from 13.9 g (49.2 mmol)of 2-chloro-4-iodobenzoic acid, 11.52 g (79%) of the expected methylester were obtained in the form of an oil.

(c) Preparation of methyl 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl)benzoate

Following the basic procedure of Example 11(d), by reacting 1.2 g (5mmol) ofα-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanolwith 1.6 g (5 mmol) of methyl 2-chloro-4-iodobenzoate, 1.7 g (83%) ofthe expected ester was obtained in the form of a brown oil.

(d) Synthesis of 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

Following the basic procedure of Example 12(b), from 1.7 g (4.1 mmol) ofmethyl 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate,730 mg (44%) of 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid, with a melting point of 145°-148° C., were obtained.

EXAMPLE 53 Preparation of 2-acetoxy-4-3-acetoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid

500 mg (1.3 mmol) of2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid and 10 ml of pyridine were introduced into a round-bottomed flaskand 150 μl (1.56 mmol) of acetic anhydride were added dropwise. Stirringwas carried out at room temperature for 2 hours, the reaction mixturewas evaporated to dryness and the residue was taken up in water andacidified to a pH of 4. Extraction was carried out with ethyl ether,drying was carried out over magnesium sulfate and evaporation wascarried out. The residue obtained was purified by chromatography on asilica column eluted with ethyl ether. 230 mg (39%) of2-acetoxy-4-(3-acetoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid, with a melting point of 113°-115° C., were recovered.

EXAMPLE 54 Preparation of methyl 4-3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl!benzoate

(a) Preparation of 3-tert-butyl-4-propyloxybromobenzene

Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02mol) of 3-tert-butyl-4-hydroxybromobenzene with 2.2 ml (0.022 mol) of1-iodopropane, 4.7 g (87%) of 3-tert-butyl-4-propyloxybromobenzene wereobtained in the form of a colorless oil.

(b) Preparation of 3-tert-butyl-4-propyloxybenzaldehyde

Following the basic procedure of Example 11(a), from 4.5 g (16.6 mmol)of 3-tert-butyl-4-propyloxybromobenzene, 3.65 g (100%) of the expectedaldehyde were obtained in the form of a slightly yellow oil.

(c) Preparation ofα-trimethylsilylethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol

Following the basic procedure of Example 11(b), by reacting 3.6 g (16.4mmol) of 3-tert-butyl-4-propyloxybenzaldehyde with one equivalent oflithium trimethylsilylacetylide, 5.2 g (100%) of the expected alcoholwere obtained in the form of a colorless oil.

(d) Preparation of α-ethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol

Following the basic procedure of Example 11(c), from 5.1 g (14.1 mmol)of α-trimethylsilylethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol,there were obtained, after chromatography on a silica column eluted witha mixture of dichloromethane and heptane (60/40), 3.3 g (80%) ofα-ethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol in the form of ayellow oil.

(e) Synthesis of methyl 4-3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 3.3 g (13.4mmol) of α-ethynyl-3-tert-butyl-4-(propyloxy)benzenemethanol with 3.8 g(13.4 mmol) of methyl 2-hydroxy-4-iodobenzoate, 4.4 g (83%) of methyl 4-3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl!benzoate wereobtained in the form of a dark brown oil.

EXAMPLE 55 Preparation of methyl 4-3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl!benzoate

(a) Preparation of 3-tert-butyl-4-hexyloxybromobenzene

Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02mol) of 3-tert-butyl-4-hydroxybromobenzene with 3.3 ml (0.022 mol) of1-iodohexane, 6 g (97%) of 3-tert-butyl-4-hexyloxybromobenzene wereobtained in the form of a colorless oil.

(b) Preparation of 3-tert-butyl-4-hexyloxybenzaldehyde

Following the basic procedure of Example 11(a), from 5.9 g (18.8 mmol) )of 3-tert-butyl-4-hexyloxybromobenzene, 4.9 g (100%) of the expectedaldehyde were obtained in the form of a slightly yellow oil.

(c) Preparation ofα-trimethylsilylethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol

Following the basic procedure of Example 11(b), by reacting 4.8 g (18.3mmol) of 3-tert-butyl-4-hexyloxybenzaldehyde with one equivalent oflithium trimethylsilylacetylide, 6.6 g (100%) of the expected alcoholwere obtained in the form of a colorless oil.

Preparation of α-ethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol

Following the basic procedure of Example 11(c), from 6.6 g (18.3 mmol)of α-trimethylsilylethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol,there were obtained, after chromatography on a silica column eluted witha mixture of dichloromethane and heptane (60/40), 4.3 g (81%) ofα-ethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol in the form of ayellow oil.

(e) Synthesis of methyl 4-3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl!benzoate

Following the basic procedure of Example 11(d), by reacting 3.8 g (13.2mmol) of α-ethynyl-3-tert-butyl-4-(hexyloxy)benzenemethanol with 3.7 g(13.7 mmol) of methyl 2-hydroxy-4-iodobenzoate, 4 g (69%) of methyl 4-3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl!benzoate wereobtained in the form of a dark brown oil.

EXAMPLE 56

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

(A) ORAL ROUTE

    ______________________________________                                        (a) 0.2 g Tablet:                                                             (i) Compound prepared in Example 7                                                                     0.001 g                                              (ii) Starch              0.114 g                                              (iii) Dicalcium phosphate                                                                              0.020 g                                              (iv) Silica              0.020 g                                              (v) Lactose              0.030 g                                              (vi) Talc                0.010 g                                              (vii) Magnesium stearate 0.005 g                                              (b) Oral suspension in 5 ml ampoules:                                         (i) Compound prepared in Example 3                                                                     0.001 g                                              (ii) Glycerin            0.500 g                                              (iii) Sorbitol at 70%    0.500 g                                              (iv) Sodium saccharinate 0.010 g                                              (v) Methyl parahydroxybenzoate                                                                         0.040 g                                              (vi) Flavoring           qs                                                   (vii) Purified water qs  5 ml                                                 (c) 0.8 g Tablet:                                                             (i) Compound of Example 6                                                                              0.500 g                                              (ii) Pregelatinized starch                                                                             0.100 g                                              (iii) Microcrystalline cellulose                                                                       0.115 g                                              (iv) Lactose             0.075 g                                              (v) Magnesium stearate   0.010 g                                              (d) Oral suspension in 10 ml ampoules:                                        (i) Compound of Example 2                                                                              0.200 g                                              (ii) Glycerin            1.000 g                                              (iii) Sorbitol at 70%    1.000 g                                              (iv) Sodium saccharinate 0.010 g                                              (v) Methyl parahydroxybenzoate                                                                         0.080 g                                              (vi) Flavoring           qs                                                   (vii) Purified water qs  10 ml                                                ______________________________________                                    

(B) TOPICAL ROUTE:

    ______________________________________                                        (a) Ointment:                                                                 (i) Compound of Example 9                                                                              0.020 g                                              (ii) Isopropyl myristate 81.700 g                                             (iii) Fluid paraffin oil 9.100 g                                              (iv) Silica ("Aerosil 200",                                                                            9.180 g                                              marketed by DEGUSSA)                                                          (b) Ointment:                                                                 (i) Compound of Example 10                                                                             0.300 g                                              (ii) Petroleum jelly     100 g                                                (c) Nonionic water-in-oil cream:                                              (i) 2-Hydroxy-4- 3-hydroxy-3-(3-tert-                                                                  0.100 g                                              butyl-4-hydroxyphenyl)-1-                                                     propynyl!benzoic acid                                                         (ii) Mixture of emulsive lanolin                                                                       39.900 g                                             alcohols, waxes and oils                                                      ("anhydrous Eucerin" marketed                                                 by BDF)                                                                       (iii) Methyl parahydroxybenzoate                                                                       0.075 g                                              (iv) Propyl parahydroxybenzoate                                                                        0.075 g                                              (v) Sterile demineralized water qs                                                                     100 g                                                (d) Lotion:                                                                   (i) Compound of Example 8                                                                              0.100 g                                              (ii) Polyethylene glycol (PEG 400)                                                                     69.900 g                                             (iii) Ethanol at 95%     30.000 g                                             (e) Hydrophobic ointment:                                                     (i) Compound of Example 7                                                                              0.300 g                                              (ii) Isopropyl myristate 36.400 g                                             (iii) Silicone oil ("Rhodorsil 47 V                                                                    36.400 g                                             300" marketed by RHONE-POULENC)                                               (iv) Beeswax             13.600 g                                             (v) Silicone oil ("Abil 300.000 cst"                                                                   100 g                                                marketed by GOLDSCHMIDT)                                                      (f) Nonionic oil-in-water cream:                                              (i) Compound of Example 3                                                                              1.000 g                                              (ii) Cetyl alcohol       4.000 g                                              (iii) Glycerol monostearate                                                                            2.500 g                                              (iv) PEG 50 stearate     2.500 g                                              (v) Shea butter          9.200 g                                              (vi) Propylene glycol    2.000 g                                              (vii) Methyl parahydroxybenzoate                                                                       0.075 g                                              (viii) Propyl parahydroxybenzoate                                                                      0.075 g                                              (ix) Sterile demineralized water                                                                       100 g                                                ______________________________________                                    

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A polyaromatic propynyl compound having thestructural formula (I): ##STR7## in which X is one of the radicals:##STR8## Ar is a radical of the following formula (a): ##STR9## R₁ is(i) a hydrogen atom, (ii) a radical --CH₃, (iii) a radical --CH₂--O--R₆, (iv) a radical --O--R₆, (v) a radical --CO--R₇, or (vi) aradical--S(O)_(t) R₉ ; R₂ and R₃ together form, with the carbon atomsfrom which they depend, a 5- or 6-membered ring optionally substitutedby methyl groups and/or optionally interrupted by an oxygen or sulfuratom; R₄ is a hydrogen atom, a halogen atom, a lower alkyl radical or aradical --OR₆ ; R₅ has the definition of R₄, and R₄ and R₅ may beidentical or different; R₆ is a hydrogen atom, a lower alkyl radical ora radical --CO--R₉ and further wherein the radicals R₆ may be identicalor different; R₇ is (a) a hydrogen atom, (b) a lower alkyl radical, (c)a radical of the formula: ##STR10## or (d) a radical --OR₈ wherein R₈ isa hydrogen atom, a linear or branched alkyl radical having from 1 to 20carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical,or a phenyl, benzyl or phenethyl radical, which are optionallysubstituted by at least one halogen atom, or a hydroxyl or nitrofunctional group; R₉ is a lower alkyl radical; R₁₀ is a hydrogen atom, alower alkyl radical, or a radical --OR₆ ; R₁₁ is a radical --OR₆ ; R'and R", which may be identical or different, are each a hydrogen atom, alower alkyl radical, a mono or polyhydroxyalkyl radical, or a phenylradical optionally substituted by at least one halogen atom, or ahydroxyl or nitro functional group, or R' and R" together with thenitrogen atom attached may form a piperidino, morpholino, pyrrolidino orpiperazino radical which are optionally substituted at the 4-position bya C₁ -C₆ alkyl radical or a mono- or polyhydroxyalkyl radical; t is aninteger equal to 0, 1 or 2; and the radicals R₁₀ and R₁₁ may togetherform a single oxo group of the formula ═O; orpharmaceutically/cosmetically acceptable salt or optical or geometricisomer thereof.
 2. A polyaromatic propynyl compound as defined by claim1, wherein formula (I), X is the radical: ##STR11##
 3. A polyaromaticpropynyl compound as defined by claim 1, wherein formula (I), X is theradical: ##STR12##
 4. A polyaromatic propynyl compound as defined byclaim 1, comprising a pharmaceutically acceptable salt thereof.
 5. Apolyaromatic propynyl compound as defined by claim 1, wherein formula(I), R₅ is an --OH group, R₇ is a radical --OR₈, and R₁₁ is a radical--OR₆.
 6. A polyaromatic propynyl compound as defined by claim 1,wherein formula (I), the lower alkyl radical substituents are selectedfrom the group consisting of methyl, ethyl, isopropyl, butyl, tert-butyland hexyl radicals.
 7. A polyaromatic propynyl compound as defined byclaim 1, wherein formula (I), the linear or branched alkyl radicalsubstituents having from 1 to 20 carbon atoms are selected from thegroup consisting of methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl,hexadecyl and octadecyl radicals.
 8. A polyaromatic propynyl compound asdefined by claim 1, wherein formula (I), the monohydroxyalkyl radicalsubstituents are selected from the group consisting of 2-hydroxypropyland 3-hydroxypropyl radicals.
 9. A polyaromatic propynyl compound asdefined by claim 1, wherein formula (I), the polyhydroxyalkyl radicalsubstituents are selected from the group consisting of2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyland pentaerythritol radicals.
 10. A polyaromatic propynyl compound asdefined by claim 1, wherein formula (I), the alkenyl radicalsubstituents have from 1 to 5 carbon atoms and comprise at least onesite of ethylenic unsaturation.
 11. A polyaromatic propynyl compound asdefined by claim 1, wherein formula (I), the halogen atom substituentsare selected from the group consisting of fluorine, chlorine and bromineatoms.
 12. A pharmaceutical composition of matter, comprising atherapeutically effective amount of a polyaromatic propynyl compound asdefined by claim 1, or pharmaceutically acceptable salt or isomerthereof, and a pharmaceutically acceptable carrier or diluent therefor.13. The pharmaceutical composition as defined by claim 12, furthercomprising a retinoid compound, a D vitamin, a corticosteroid, ananti-free radical agent, an α-hydroxy or α-keto acid, an ion channelblocker, or combination thereof.
 14. The pharmaceutical composition asdefined by claim 12, comprising a tablet, a capsule, a syrup, asuspension, an elixir, a solution, a powder, granules, an emulsion,microspheres, nanospheres, lipid vesicles, or polymeric vesicles. 15.The pharmaceutical composition as defined by claim 12, comprising anointment, a cream, a milk, a pommade, an impregnated pad, a gel, aspray, or a lotion.
 16. The pharmaceutical composition as defined byclaim 12, which is suitable for topical administration.
 17. Thepharmaceutical composition as defined by claim 12, which is suitable forsystemic administration.
 18. The pharmaceutical composition as definedby claim 12, comprising from 0.001% to 5% by weight of said polyaromaticpropynyl compound, or salt or isomer thereof.
 19. A cosmetic compositionof matter, comprising a cosmetically effective amount of a polyaromaticpropynyl compound as defined by claim 1, or cosmetically acceptable saltor isomer thereof, and a cosmetically acceptable carrier or diluenttherefor.
 20. The cosmetic composition as defined by claim 19,comprising a cream, a milk, a lotion, a gel, microspheres, nanospheres,lipid vesicles, polymeric vesicles, a soap, or a shampoo.
 21. Thecosmetic composition as defined by claim 19, comprising from 0.001% to3% by weight of said polyaromatic propynyl compound, or salt or isomerthereof.
 22. The cosmetic composition as defined by claim 19, furthercomprising a retinoid compound, a D vitamin, a corticosteroid, ananti-free radical agent, an α-hydroxy or α-keto acid, an ion channelblocker, or combination thereof.
 23. The pharmaceutical composition asdefined by claim 12, further comprising a wetting agent, a depigmentingagent, a moisturizing agent, an antiseborrhoeic or antiacne agent, anantibiotic, an antifungal agent, a hair regrowth promoter, anon-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriaticagent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or esteror amide thereof, or combination thereof.
 24. The pharmaceuticalcomposition as defined by claim 12, further comprising a taste- orflavor-enhancing agent, a preservative, a stabilizer, a moistureregulating agent, a pH regulating agent, an osmotic pressure modifyingagent, an emulsifying agent, a UV-A or UV-B screening agent, anantioxidant, or combination thereof.
 25. The cosmetic composition asdefined by claim 19, further comprising a wetting agent, a depigmentingagent, a moisturizing agent, an antiseborrhoeic or antiacne agent, anantibiotic, an antifungal agent, a hair regrowth promoter, anon-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriaticagent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or esteror amide thereof, or combination thereof.
 26. The cosmetic compositionas defined by claim 19, further comprising a taste- or flavor-enhancingagent, a preservative, a stabilizer, a moisture regulating agent, a pHregulating agent, an osmotic pressure modifying agent, an emulsifyingagent, a UV-A or UV-B screening agent, an antioxidant, or combinationthereof.
 27. A polyaromatic propynyl compound as defined by claim 1,wherein R₂ and R₃ form, together with the carbon atoms from which theydepend, a 6-membered ring.
 28. A polyaromatic propynyl compound asdefined by claim 1, wherein R₂ and R₃ form, together with the carbonatoms from which they depend, a 6-membered ring substituted by methylgroups.
 29. A polyaromatic propynyl compound as defined by claim 1,wherein R₂ and R₃ form, together with the carbon atoms from which theydepend, a 6-membered ring interrupted by an oxygen or sulfur atom.
 30. Apolyaromatic propynyl compound as defined by claim 1, wherein R₄ is ahydrogen atom or a radical --OR₆ wherein R₆ is a lower alkyl radical.31. A polyaromatic propynyl compound selected from the group consistingof methyl 4-3-oxo-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 2-hydroxy-4-3-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoate;2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 2-hydroxy-4-3-oxo-(3-tert-butyl-4-methoxyphenyl)-1-propynyl!benzoic acid; 4-1-oxo-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid; 4-1-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoate;2-hydroxy-4-(3-oxo-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoicacid; 4- 3-hydroxy-3-(3-tert-butyl-4-methoxyphenyl)- 1-propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoate; 4-1-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-2-propynyl!benzoic acid;2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoic acid;2-hydroxy-4-3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoic acid;(+)-isomer of methyl4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;(-)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; (+)-isomer of methyl-2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;(-)-isomer of 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; (-)-isomer of methyl 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;(-)-isomer of methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;(+)-isomer of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; (+)-isomer of2-hydroxy-4-(3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;2-hydroxy-4-3-hydroxy-3-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-1-propynyl!benzoicacid; 2-methoxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzaldehyde;4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzylacetate; 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzenemethanol; 4-3-hydroxy-3-(5,6,8,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!toluene;4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,7,8-pentamethyl-2-naphthyl)-1-propynyl!phenylacetate; 4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!phenol;4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfinylmethane;4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!phenylsulfonylmethane;N-ethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide;N,N'-diethyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzamide;morpholide of 4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoate;2-hydroxy-4-3-hydroxy-3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)-1-propynyl!benzoicacid; methyl 2-hydroxy-4-3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoate;2-hydroxy-4-(3-hydroxy-3-(3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 4- 3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl!benzoicacid; 4- 3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl!benzoicacid; methyl 3-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!-benzoate;-methyl-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; 2-chloro-4-3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl!benzoicacid; and 2-acetoxy-4-3-acetoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1propynyl!benzoicacid ; methyl 4-3-hydroxy-3-(3-tert-butyl-4-propyloxyphenyl)-1-propynyl!benzoate; andmethyl 4-3-hydroxy-3-(3-tert-butyl-4-hexyloxyphenyl)-1-propynyl!benzoate!.